IE44373B1

IE44373B1 - Pyridthione derivatives

Info

Publication number: IE44373B1
Application number: IE1524/76A
Authority: IE
Original assignee: Nyegaard & Co As
Priority date: 1975-07-10
Filing date: 1976-07-09
Publication date: 1981-11-04
Also published as: US4246266A; NO144987C; AU1577376A; BE843996A; FR2316948A1; SE433556B; NO762409L; CH626228A5; JPS5227776A; DE2631050A1; ZA764106B; NO144987B; CA1104137A; GB1554720A; DK310276A; AU503672B2; FI762014A; SE7607896L; NL7607614A; ES449705A1

Abstract

Antimicrobial compositions comprising as active ingredient at least one compound of the general formula I (wherein R1 and R5, which may be the same or different each represent a hydrogen or halogen atom and R2, R3 and R4 which may be the same or different, each represent a hydrogen atom or a lower alkyl group) in association with an antimicrobial carrier, excipient or diluent. The compounds of formula I may be prepared by reacting a corresponding dihydrothiazolo 8-oxide compound with a base. Certain of the compounds of formula I are novel and may also be prepared by pyrolytic decarboxylation of a corresponding carboxyl substituted thiazolo-8-oxide compound.

Description

This invention relates to antimicrobial ccmpositicns for use in medicine and in agriculture.: We have found that certain pyridthiones possess interesting activity against dermatophytes coupled with a freedom from neurotoxicity or any tendency to cause skin Irritation or sensitisation. The activity of the abovementioned pyridthiones against plant fungi also enables these compounds to he formulated into agricultural compositions for use, for example, against mildew.

According to the present invention there are thus provided antimicrobial compositions comprising as active ingredient at least one compound of the general formula ent each represent a hydrogen or halogen atom and 2 3 4 R , R and R which may be the same or different, -244373 each represent a hydrogen atom or an alkyl group with 1 to 5 carbon atoms) in association with an inert carrier, excipient or diluent.

Where R^ and are different the possibility of 5 cis/trans isomerism exists. It will be appreciated that both such forms of the compounds of formula I fall within the scope of the present invention.

According to one embodiment of the present invention we provide pharmaceutical and veterinary compositions containing as active ingredient a compound of the general formula (where R^ and R^, which may be the same or different,each 2 3 λ represent a hydrogen or halogen atom and R , RJ and R4 which may be the same or different, each represent a hydrogen atom or an alkyl group with 1 to 5 carbon atoms) in association -344373 with a pharmaceutical carrier or excipient. Bromine and chlorine are preferred halogens for the substituents R^ and r5.r5, however, is preferably hydrogen. Lower alkyl substituents have 1-5 carbon atoms, and may, for example be methyl, ethyl, isopropyl or butyl groups, a methyl group being preferred.

The new compounds possess an unusually broad spectrum of antifungal and antibacterial activity, being effective, for example, against Staphylococcus aureus as well as a range of fungi, such as Candida albicans and the dermatophytes Penicilllum patulum, Trichophyton mentagrophytes and Microsporum canis.

The widely used antifungal agent tolnaftate has, in contrast, no antibacterial activity and is inactive against Candida albicans.

The new compounds thus make possible general purpose antifungal topical formulations in contrast to the previously used specialised antifungal preparations.

Particularly useful compounds as active ingredient 20 are those in which (a) all of R^, R^, r^ and R$ represent hydrogen, or (b) represents a halogen atom -444373 rt rt t C while R , R , ά and R represent hydrogen or (c) one of R2, R3 and R4 represents a methyl group while the other two represent hydrogen and R^ and R3 represents hydrogen or (d) r\ R2, R3 and R^ represent hydrogen atoms and R3 represents a chlorine atom.. Especially noteworthy compounds thus include N-vinyl-3-hydroxy-pyrid-2-thione, Nvinyl-4-bromo or N-vinyl-4-chloro-3-hydroxy-pyrid-2-thione, N-propyl-1 ‘-en-l-yl-3-hydroxy-pyrid-2-thione, N-prop-2-en-2yl-3-hydroxy-pyrid-2-thione and N-vinyl-6-chloro-310 hydroxy-3-pyrid-2-thione.

The compositions according to the present invention may be formulated for application topically or by any other suitable route. Compositions for veterinary or human use could include drops, lotions, creams or ointments for the treatment of ears or for general skin infections; pressure sprays for application either topically to the skin or to the mucous membranes of the nose, throat and bronchii.

For materials which show oral activity, forms of administration may be tablets, capsules or liquid preparations. 2° The various compositions may include additional active ingredients such as other antimicrobial compounds and antiinflammatory steroids e.g. hydrocortisone. Compositions -544373 may also include absorption prompting agents such as dimethyl sulphoxide and materials which enhance or have a synergist ic effect on the activity of the compounds of this invention.

Topical application is particularly advantageous and thus suitable formulations include creams, lotions and dusting powders.

Conventional or cosmetic bases may be employed for the preparation of ear drops, lotions, creams, hydrophobic and hydrophilic ointments. Nasal drops and pressure sprays for application to the mucous membranes of the nose, threat and bronchial tissues, may have the active ingredients .dissolved or suspended in the bases, which may include non-toxic propellants for use in aerosol spray packs.

Conventional tabletting agents may include inert diluents and fillers such as starch, sugars, alcohols or mineral carriers; binding agents such as syrup, acacia and cellulose derivatives; disintegrating agents e.g, potato starch and surfactants such as polyethylene glycols; lubricating materials e.g. magnesium stearate, talc, and -644373 finely dispersed silicon dioxide. Tablets may be engraved during compression for identification and/or coated by conventional processes such as sugar or film coating. Creams, ointments and lotions suitably contain 0.2 to 5.0% by weight of the active ingredient of formula I, advantageously 0.5 to 2.0%. Aerosols should suitably contain 0.02 to 1% by weight, advantageously 0.05 to 0.5%; while dusting powders suitably contain 0.1 to 3.0%, advantageously about 1% by weight.

As stated above the compounds of formula X are also of potential interest as active ingredients in compositions for use against plant fungal pathogens such as mildew.

Thus in one embodiment of the present invention we provide agricultural compositions comprising as active ingredient at least one compound of formula 1 as hereinbefore defined in association with a non-phytotoxic carrier or diluent.

The new compounds according to the invention can be formulated for use in any desired way. Such formulations will include the compound in association with a 7' non-phytotoxic carrier or diluent. Such carriers may be liquid or solid and designed to aid the application of the compounds either by way of dispersing it where it is to be applied or to provide a formulation which can be made by the user into a dispersible preparation.

Liquid preparations thus include preparations of the compound in the form of emulsifiable concentrates, solutions or emulsions which can he used on their own or be. adapted to be made up with water or other diluents to 10 form sprays in such cases the carrier is a solvent or emulsion base non-phytotoxic under the conditions of use. Generally such preparations will include a wetting, dispersing or emulsifying agent. Other liquid preparations include aerosols in which the compound is associated with a liquid carrier or propellant.

Solid preparations include dusts and wettable powders, granulates and pellets, mordant powders, and semi-solid preparations such as pastes. Such preparations may include inert solid or liquid diluents such as clays, which may themselves have wetting properties, and/or wetting, dispersing or emulsifying agents; binding and/or -844373 adhesive agents may also be included. Solid preparations also include thermal fumigating mixtures wherein the compound is associated with a solid pyrotechnic component.

Compositions according to the present invention, in liquid form preferably contain from 0.01% to 5 especially from 0.05 to 1.0 % by weight of active ingredient.

In ultra-low volume formulations and dusts higher active ingredient concentrations are, in general, used e.g. 5 to 15 % by weight.

According to a further feature of the present invention there is provided a method of preventing or inhibiting the growth or proliferation of bacteria or fungi which comprises applying to a non-human site to be protected against infection by bacteria or fungi or already infected by bacteria or fungi an effective amount of a pharmaceutical or veterinary composition as hereinbefore defined.

We also provide a method of preventing or inhibiting the growth or proliferation of mildew which comprises applying to a site to be protected against infestation by mildew or already infested by mildew an effective amount u jl of aft agricultural composition as hereinbefore defined.

Many of the compounds of the formula I are novel compounds constituting a further feature of the present invention, namely compounds of the general formula I as 12 5 defined above in which R , R and R do not all represent A hydrogen atoms when either one of RJ and u represents a hydrogen atom while the other represents a methyl group 3 4 or both R and R represents a hydrogen atom. The 12 5 compounds in which R , R and R are all hydrogen and 3 4 either one of RJ and R* is hydrogen while the other is 4 methyl or both R5 and R^ are hydrogen have only been described previously in relation to chemical investigations and their possible utility in medicine or, indeed, --'-'— --any—oth’ei' utiTity'has not been suggested. Preferred compounds according to the present invention, hy virtue of their antimicrobial activity, include the following: N-viny1-4-bromo-3-hydroxy-pyrid-2-thione, N-vinyl-4-chloro-3-hydroxy-pyrid-2-thione, N-prop-2'-en-2-yl-3-hydroxy-pyrid-2-thione and N-vinyl-6«chloro-3-hydroxy-pyrid-2-thione. 2 Furthermore, the two compounds in which R , R -1044373 3 4 and κ are all hydrogen and one of R and R* is methyl while the other is hydrogen, namely cis- and transN-prop-l-en-lLyl-3-hydroxy-pyrid-2-thione have only been described in admixture.

Trans-N-prop-1 ‘-en-l'-yl-3-hydroxy-pyrid-2-thione substantially free from the cis - isomer thereof constitutes a further feature of the present invention.

We have also found a novel process for the preparation of compounds of the general formula I and this constitutes a still further feature of the present invention.

The process according to the invention comprises reaction of a compound of the general formula 3 4 or an acid addition salt thereof (where RA, R , R , R* and r5 are as defined for formula I above) with a base 2 whereby the proton adjacent to R is abstracted and the dihydrothiazolo ring is opened. The acid addition salts -1144373 may be formed, for example, with mineral acids such as J hydrohalic acids, e.g. hydrogen bromide or hydrogen chloride. 4 In this reaction, when R and R are different, a 5 compound in which the pyridine ring is trans to the larger of RJ and R4 is the generally favoured product. Suitable bases include lithium alkyls such as lithium t-butyl and lithium-nitrogen derivatives such as lithium diisopropylamide; alkali metals in liquid ammonia or a liquid amine; alkali metal hydroxides and alkali metal oxides. The anion of the base is preferably bulky to avoid or reduce nucleophilic attack. A reagent of choice generally applicable in all cases is an alkali metal t-butoxide, especially potassium t-butoxide.

The reaction is conveniently effected in a polar solvent such as dialkylformamide or dialkylacetamide or a tertiary alcohol, e.g. t-butanol or the reaction medium can comprise an excess of the base medium, e.g. ammonia or an amine. The reaction proceeds well at ambient temperature and yields of 70-80% may be obtained.

The new compounds according to the present invention 1244373 may also be prepared by any other convenient method, in particular by pyrolytic decarboxylation under anhydrous conditions of compounds of the general formula (III) where R^-R^ are as defined above and r\ R^ and do not all represent hydrogen atoms when either one of R and R^ represents a hydrogen atom while the other represents 3 4 a methyl group or both R and R represent a hydrogen atom or an alkyl group, or a salt thereof. The pyrolysis is advantageously effected at a temperature of from 150-180°C at reduced pressure. The starting material is conveniently ground together with quartz sand or, in the case of a salt with a strong acid, an anhydrous alkali metal carbonate, e.g. potassium carbonate.

A Where R and R4 are different, a mixture of cis and trans isomers is obtained in this reaction.

Both cis and trans isomers possess activity. -1344373 The dihydr0thiazolo[3,2-a]pyridinium starting I materials of formulae II and III may be prepared by methods known in the chemical literature, e.g. by reaction of a pyrid-2-thione with a 1,2-dihaloalkane or 1,2-dihalo5 alkanoic acid, or a 2-halopyridine with a l-halo-2mercapto alkane or -alkanoic acid. R^ and R$ when halogen atoms, may be introduced by halogenation of the product of such a reaction.

The following Examples illustrate the invention 10 further. -1444373 Preparation of starting materials ,7-Dlbromodlhydrothlazolo[3.2-a]pyridinium-8-oxide hydrobromide Bromine (16.0 g, 0.10 mole) in methanol (100 ml) was added dropwise at room temperature to a solution of dihydrothiazolo[3,2-a]pyridinium-8-oxide hydrobromide (11.85 g, 0.05 mole) in methanol (200 ml). The precipitated product was collected the next day; yield 12.0 g (66%), m.p. 280°C (decom.). The product was recrystallised from aq. HBr for elemental analysis. (Found: C 20.62; H 2.10 Calcd. for C-J^B^NOS. HBr.HgO: C 20.47; H 1.95); τ (TFA) 6.0 (S-CH2), 4.6 (N-CH2), 2.0 (H-6). 7-Broniodihydrothiazolo[3,2-a]pyridlnium-8-oxide hydrobromide Bromine (4.8 g, 0.03 mole) in methanol (70 ml) at -70°C was added dropwise over 10 h to a solution of dihydrothiazolo[3,2-a]pyridinium-8-oxide hydrobromide (7.0 g, 0.03 mole) in methanol (600 ml) at -70°C. The solution was then allowed to reach room temperature and evaporated. The residual material was recrystallized three times from small volumes of water; yield: 3.0 g (32%); m.p. 245°C (decomp.). (Found: C 26.84; H 2.61; Calcd. for 1544373 C^HgBrNOS. HBr; C 26.86; H 2.25); τ (TFA) 6.1 (S-CH2), 4.8 (N-CH2), 2.3 and 1.9 (pyridine, AB, J « 6.5 Hz). 7- Chlorodlhydrothiazolof3,2-a]pyridinium-8-oxide hydrobromide A solution of 7-bromodihydrothiazolo[3,2-a]pyridinium8- oxide (2.0 g, 0.006 mole) in DMF (175 ml) at 90°C was saturated with sodium chloride and kept at this temperature for 4 h. The solution was then allowed to cool to room temperature and the precipitated salt removed before 10 evaporation at reduced pressure of the filtrate. The residue was triturated with ether and recrystallized from a small volume of water; yield: 0.9 g (63%); m.p.> 270°C (decomp.). (Found: C 31,22; H 2.88. Calcd. for C^HgCl NOS.HBr C 31.20; H 2.66) τ (TFA) 6.1 (S-CHj), 4.8 (N-CH2), 2.4 and 1.8 (pyridine, AB, J = 6.5 Hz). ,7-Dichlorodihydrothiazolo[3,2-a]pyridinium-8-oxide a) hydrobromide:The title compound was prepared in the same way as the 7-chloro derivative above; 5,7-dibromodihydrothiazolo [3,2-a]pyridinium-8-oxide hydrobromide in DMF saturated with sodium chloride was heated at 90°C for 4 hr. The -1644373 product was worked up as above and recrystallised from water; Yield 55%, m.p. 275°C (decomp.). (Found: C 27.58; H 2.07. Calc, for C^C^NOS.HBr; C 27.81; H 1.98) τ (TFA) 6.0 (S-CHg), 4.7 (N-CHg), 2.4 (pyridine singlet). b) betaine:5-Chloro-7-nitrodihydrothiazolo[3,2-a]pyridinium-8oxide was prepared from 5-chlorodihydrothiazolo[3,2-a]. pyridinium-8-oxide (5.0 g, 0.03 mol) dissolved in acetic acid (100 ml) by the dropwise addition of a solution of fuming nitric acid (5 ml) and concentrated sulphuric acid (4 ml) in acetic acid (50 ml) with stirring at room temperature. The reddish precipitate of 5-chloro-7nitrodihydrothiazolo[3,2-a]pyridinium»8-oxide was recrystallized from ethanol; yield 60%, m.p. 180-190°C (decomp.) (Found: C 36.11; H 2.46. Calc, for C^HgClNgO^S: C 36.20; H 2.16) τ (TFA) 5.9 (S-CHg), 4.5 (N-CHg), 1.85 (H-pyridine).

The 5,7-dichloro derivative was prepared by heating under reflux a solution of 5-chloro-7-nitrodihydrothiazolo [3,2-a]pyridinium-8-oxide (1.1 g, 0.005 mol) and zinc chloride (2.0 g) in 3N HCl (50 ml) for 3 days. The -1744373 solution was then evaporated, the residue dissolved in I water and the aqueous solution neutralized with NaOH before being passed through a cation exchange column (IR120 %nberlite in H+-form). The chloride ions were removed by elution with water, and the desired substance was eluted with 0.6N aq. ammonia. Evaporation of the NH^eluates left the betaine; yield 78%, m.p. 220-225°C (decomp.).. The identity of the compound was verified by spectroscopic and chromatographic comparison with the hydrobromide synthesized according to (a).

-Chlorodihydrothiazolo[3.2-a]pyridlnium-8-oxide hydrochloride Dihydrothiazolo[3,2-a]pyridinium-8-oxide (0.45 g, 0.003 mol) was dissolved in DMF (125 ml) and the solution cooled to -60®C. Sulphuryl chloride (1.0 ml) was then added dropwise to this solution at -60° with stirring.

When the addition was completed, the reaction mixture was slowly allowed to reach room temperature overnight. Addition of a little water to the reaction mixture was followed by evaporation under reduced pressure to a small volume. The title compound crystallized out from the -18*Amberlite is a trade mark solution in 48% yield (0.32 g); the sample for elemental analysis was recrystallized from a small volume of water, m.p. 270°C (decomp.). (Found: C 37,41; H 3.19. Calc, for C^HgClNOS.HCl: C 37.50; H 3.12); τ (TFA) 6.1 (S-CH2), 4.7 (N-CHj), 2.6 and 2.3 (pyridine, AB, J 8.5 Hz). -19Example 1 N-Vinyl-3-hydroxypyrid-2-thione a) DMF-solvent; A solution of 0.5M potassium tert.-butoxide in tert.-butanol (75 ml, 0.038 mole) was added dropwise over h at room temperature to a stirred solution of dihydrothiazolo[3,2-a]pyridinium-8-oxide (4.6g, 0.03 mole) in DMF (400 ml). Acetic acid was then added until acid pH and the reaction mixture evaporated at reduced pressure.

The residual material was triturated with water (20 ml) and the insoluble title material filtered off; yield 3.2 g (70%). b) tert.-Butanol solvent; Dihydrothlazolo[3,2-a]pyridinium-8-oxide (13.8 g, 0.09 mole) was added to 0.5M potassium tert.-butoxide in tert.-butanol (450 ml, 0.23 mole) and the reaction mixture stirred at room temperature overnight. Acetic acid (13 ml) was then added until acid pH and the reaction mixture evaporated at reduced pressure. The residual material was triturated with water (35 ml) and the insoluble title compound collected by filtration; yield 9.7 g (70%), m.p. 84°C (EtOH). (Found: C 55.09; H 4.83 Calcd. for C?H7N0S: C 54.90; H 4.61). τ 4.7 (J - 8.5 Hz) and 4.5 (J - 16 Hz; -CH„, J - 2 Hz), 2.1 (CH-N) 2.3 2 gem 2.5 and 3.0 and 3.4 (pyridine); λ (EtOH) 378 (log ε uidX 3.97). 274 sh. (3.80) and 261 nm (3.81).

TLC on silica gel: n-BuOH: EtOH 0.88NH^ (8 : 2 : l) Rf - 0.55 - 0.6 PhMe : MeCN : HOAc (10 : 10 : 1) Rf - 0.8 - 0.85 - 21 44373 η - BuOH : EtOH (4 : 1) Rf - 0.65 Example 2 N-Vinyl-4.6-dibromo-3-hydroxypyrid-2-thione Using the method of Example 1(a) a solution of 0.5M potassium tert.-butoxide in tert.-butanol (0.004 mole, 8 ml) was added dropwise over 8 min, to a solution of 5,7-dibromodihydrothiazolo[3,2-a]pyridinium-8-oxide (0.79 g. 0.002 mole) in DMF (200 ml) at room temperature. The reaction mixture was left for another 20 min. before addition of acetic acid until acid pH. The mixture was then evaporated at reduced pressure. The residue was triturated with water and the vinyl pyridine extracted into ether. Drying and evaporation of the etherealsolution left the title compound which was further purified by recrystallization from methanol: yield 0.47 g (76%) m.p. 134°C (MeOH); (Found C 27.17; H 1.85. Calcd. for C^BrgNOS: C 27.03; H 1.62); *4.7 (J - 16 Hz) and 4.3 (J-8 Hz; -CH,, J 1.5 Hz) 3.3 2 gem (CH-N), 2.8 (pyridine).

Example 3 N-Vinyl-4-bromo-3-hydroxypyrid-2-thione In a manner analogous to Example 1(a) 7-bromo-dihydrothiazolo[3,2-a]pyridinium-8-oxide gave the above . - 22 44373 compound (79%) m.p. 127 - 128°C (MeOH). (Founds C 36.36; H 2.68. Calcd. for C^BrNOS: C 36.22; H 2.61);t(CDC13) 4.6 (J - 8.5 Hz) and 4.5 (J = 16 Hz; -CH,, J = 2 Hz) , 2.3 (N-CH··), 3.1 and 2.7 (pyridine, AB, J-7HZ).

Example 4 N-Vlnyl-4-chloro-3-hydroxypyrid-2-thione In a manner analogous to Example 1(a), 7-chlorodihydrothiazolo[3,2-a]pyridinium-8-oxide gave the above compound (67%) m.p. 132°C (MeOH). (Found: C 44.57; H 3.16;) Calcd. for C^CLNOS: C 44.78; H 3.20);t(CDC13) 4.7 (J - 8.5 Hz) and 4.6 (J - 16 Hz, -CHg, Jgem - 1.5 Hz), 2.3 (N-CH-), 3.3 and 2.7 (pyridine, AB, J - 7 Hz).

Example 5 I i N-Prop-l-en-l-yl-3-hydroxypyrid-2-thione By the method of Example 1(a), 2-methyl-dihydrothiazolo [3,2-a]pyridinium-8-oxide gave the above compound (yield 68%), m.p. 98-100nC (MeOH). (Found: C 57.45; H 5.10.

Calc, for CgHgN0S: C 57.48; Η 5.43%)τ (CDClg) 8.1 (Me, J7.0 and 1.5 Hz), 4.1 (-CH-Me), 3.3 (Ν-CH-, J - 14).

According to NMR the product has trans configuration. - 23 443 73 Example 6 N-Vinyl-6-chloro-3-hydroxpyrid-2-thione In a manner analogous to Example 1(a) 5chlorodihydrothiazolo[3,2-a]-pyridinium-8-oxide gave the above compound together with the S-vinyl analogue in 59% yield; 10-15% of the product are the vinylthio isomer.

The isomers are separated by crystallisation from methanol; the title compound crystallised out in yields corresponding to 60-70% of the crude vinyl product.

The remaining mixture of the N-vinyl and S-vinyl isomers in the methanol filtrate can be seperated on a silica·gel· column packed in N-BuOH: EtOH (4:1). The S-vinyl isomer is initially eluated.

M.p, for the title compound 100°C. (Found: C 44.89; H 3.43. Calc, for C^CINOS: C 44.78; H 5.20)j τ (CDC^) 4.6 (j-16 Hz) and 4.2 (J-8 Hz; CHg-, »1.5 Hz), 3.1 (N-CH-), 3.3 and 3.1 (pyridine, AB). - 24 443?3 Example 7 N-Vinyl-4.6-dichloro-3-hydroxypyrid-2-thione In a manner analogous to Example 1 (a) 5,7dichlorodihydrothiazolo[3,2-a]-pyridinium-8-oxide gave the title compound together with the S-vinyl analogue in 55% yield; 10-15% of the product are the S-vinyl isomer. The isomers are separated by crystallisation from methanol; the title compound crystallised out in yields corresponding to 60-70% of the crude vinyl product. M.p. 114°C (Found: C 37.08; H 2.36. Calc, for C^CljNOS: 37.85; H 2.25); τ (CDCip 4.6 (j-16 Hz) and 4.2 (J-8 Hz; CH-·, J 1.5 Hz), 3.2 (N-CH**) 3.1 (pyridine singlet), z ’ gem -25 44373 Example 8 ι t N-Prop-2-en-2-yl-3-hydroxypyrid-2-thione Reaction of 3-methyldikydrothiazolo[3,2-a]pyridinium. 8-oxide as before gave a mixture of isomers which was separated by fractional crystallisation from chloroform when the unwanted thioether was selectively precipitated.

. Evaporation · of the mother liquor and crystallisation of the residue from methanol gave the N->prop-2-en-2-yl isomer,. m.p. 93°C (Found: C 57.35; H 5.24. Calcd. for CgHgNOS: C 57.48; H 5.43); τ 7.7 (Me), 4.9 and 4.8 (J =.1 gz) (=CH2, Jgem Hz). Xmax(EtOH)373 (log e 4.06), 280 nm (3.7). · Example 9 - Propylene glycol based cream %w/w N-viny1-3-hydroxypyrid-2-thione 1.0 Cetostearyl alcohol 35.0 5 Propylene glycol 58.5 Water to 100.0 Example 1° - Polyethylene glycol based ointment %w/w N-vinyl-4-chloro-3-hydroxypyrid-2-thione 1.0 10 Polyethylene glycol 4000 to 20.0 Polyethylene glycol 400 100.0 Example 1T - Lotion %w/w N-vinyl-4-bromo-3-hydroxypyrid-2-thione 1.0 Methyl parahydroxybenzoate 0.15 Lanbritol wax 0.93 Diethylene glycol monostearate 0.65 Cetostearyl alcohol 0.65 Liquid paraffin 1.95 20 Cetomacrogol 1000 0.003 Lotion (cont) % w/w Glycerine 5.0 Isopropyl alcohol 6.5 (v/v) 5 Citric acid 0.008 Distilled water to 100.0 Example T2 - Dusting powder - - % w/w . N-propenyl-3-hydroxypyrid-2-thione 1.0 10 Maize starch ; 49.4 *Aerosil 0.15 Purified talc to 100.0 Example 13 - Aerosol preparation % w/w 15 N-vinyl-3-hydroxypyrid-2-thione 0.1 Arachis oil 10.0 Isopropyl alcohol 10.0 Trichlorofluoromethane^preon 40.0 Dichlorodifluoromethane(Freon to 100.0 20 Pressure at 25°C = - 28 - 2.2 Kg/cm2 The words *Aerosil and *Freon are trade marks Example - Anti-Mildew Concentrate % w/w N-vinyl-3-hydroxypyrid-2-thione 10 Polyethylene glycol (Macrogol 400) 90 A 0,1% aqueous solution for treating mildew was prepared by diluting the above-mentioned 10% solution in Macrogol 400 with water until the desired 0.1% aqueous solution was obtained.

Claims

CLAIMS 1. 2 in claim 1 wherein R represents a halogen atom and R , 1 5 Λ (wherein R and R , which may be the same or different

1. Antimicrobial compositions comprising as active ingredient at least one compound of the general formula Rl .OH

2. Pharmaceutical and veterinary compositions comprising 10 as active ingredient at least one compound of formula 1 as defined in claim 1 In association with a pharmaceutical carrier or excipient. 2 3 each represent a hydrogen or halogen atom and R , R and 4 R which may be the same or different, each represent a hydrogen atom or an alkyl group with 1 to 5 carbon atoms) in association with an inert carrier, excipient or diluent. 3. 4 5

3. Compositions as claimed in claim 2 which comprise as active ingredient a compound of formula I as defined in 15 claim 1 wherein R^ represents a hydrogen atom. 4. 5 R and R each represent a hydrogen atom. 35. Compositions as claimed in claim 34 which comprise N-vinyl-4-bromo-3-hydroxy-pyrid-2-thione as active ingredient. 5 36. Compositions as claimed in claim 34 which comprise N-vinyl-4-chloro-3-hydroxy-pyrid-2-thione as active ingredient. 37. Compositions as claimed in claim 30 which comprise N-prop-l-en-lLyl-3-hydroxy-pyrid*-2-thione as active

4. Compositions as claimed in claim 2 or claim 3 which comprise as active ingredient a compound of formula I as defined in claim 1 wherein R^ and/or R^ represents a chlorine or bromine atom. 5. Of from 15Q-18Q°C at reduced pressure. 67. A process as claimed in claim 65 or claim 66 whereixi the compound of formula III or salt thereof is ground together with quartz sand or in the case of a salt with a strong acid, is ground together with an anhydrous alkali 5 or an acid addition salt thereof with a base whereby the 2 proton adjacent to R is abstracted and the dihydrothiazolo ring opened such that a compound of formula I as defined in claim 1 is obtained. 55. A process as claimed in claim 54 wherein the base 10 comprises a lithium alkyl or a lithium-nitrogen derivative 56. A process as claimed in claim 55 wherein the base is lithium t-butyl or lithium diisopropylamide. 57. A process as claimed in claim 54 wherein the base comprises an alkali metal in liquid ammonia or a liquid 15 amine. 58. A process as claimed in claim54 wherein the base comprises an alkali metal hydroxide or an alkali metal alkoxide. - 38 44373 59. A process as claimed in claim 58 wherein the alkali metal alkoxj.de is an alkali metal .t-butoxide. 60. A process as claimed in claim 59 wherein the alkali metal alkoxide is potassium t-butoxide. 5 61. A process as claimed in any of claims 54-60 wherein the reaction is effected at ambient temperature. 62. A process as claimed in claim 54 substantially as herein described. 63. A process for the preparation of compounds of Ιθ formula I as defined in claim 1 substantially as herein described in any one of Examples 1-8. 64. Compounds of formula I as defined in claim 1 when prepared by a process as claimed in any of claims 54-63. 15 65. A process for the preparation of compounds of formula I as defined in claim 48 which comprises the pyrolytic decarboxylation under anhydrous conditions of compounds (wherein r\ R^, r\ R^ and R$ are as defined in claim 48) or a salt thereof. 66. A process as claimed in claim 65 wherein the pyrolytic decarboxylation is effected at : a temperature 5 said concentration is.from 0.05 to 1.0 % by weight. 43. Compositions as claimed in any of claims 29-40 in the form of ultra-low volume compositions and dusts which contain 5 to 15% by weight of active ingredient. 44. Compositions as claimed in claim 29 substantially Ιθ as herein described. 45. Agricultural compositions substantially as herein described in Example 13 . or Example 14. 46. A method of preventing or inhibiting the growth or proliferation of bacteria or fungi which comprises applyingto a •j·, non-human site to be protected a g a i ng t infection by bacteria or fungi or already infected by bacteria or fungi an effective amount of a pharmaceutical or veterinary composition as claimed in any of claims 2-28, 47. A method: of preventing or inhibiting the growth 20 or proliferation of mildew which comprises applying to a site to be protected against infestation by mildew or -36 44373 already infested by mildew an effective amount of an agricultural composition as claimed In any of claims 29-45. 48. Compounds of the general formula:5 (I)

5. Compositions as claimed in any of claims 2-4 which comprise as active ingredient a compound of formula I as defined in claim 1 wherein , R^ and/or R^ represents a methyl group. 5

6. Compositions as claimed in claim 3 which comprise as active ingredient N-vinyl-3-hydroxy-pyrid-2-thione.

7. Compositions as claimed in claim 3 which comprise as active ingredient a compound of formula I as defined

8. Compositions as claimed in claim 7 which comprise N-vinyl-4-bromo-3-hydroxy-pyrid-2-thione as active ingredient. 9. -13. 443^3 29. Agricultural compositions comprising as active ingredient at least one compound of formula I as defined in claim 1 in association with a non-phytotoxic carrier or diluent. 5 30. Compositions as claimed in claim 29 which comprise as active ingredient a compound of formula I as defined in claim 1 wherein / represents a hydrogen atom. 31. Compositions as claimed in claim 29 or claim 30 which comprise as active ingredient a compound of formula

9. Compositions as claimed in claim 7 which comprise 15 N-vinyl-4-chloro-3-hydroxy-pyrid-2-thione as active ingredient. 10. Metal carbonate prior to thermal decarboxylation. 68. A process as claimed in claim 67 wherein the alkali metal carbonate is potassium carbonate. 69. A process as claimed in claim 65 substantially as herein described, 10 ingredient. 38. Compositions as claimed in claim 30 which comprise N-prop-2-en-2-yl-3-hydroxy-pyrid-2-thione as active ingredient. 39. Compositions as claimed in claim 29 which comprise 15 N-vinyl-6-chloro-3-hydroxy-pyrid-2-thione as active ingredient. 40. Compositions as claimed in any of claims 29-39 in the form of solutions, emulsifiable concentrates, wettable powders, dusts, mordant powders, granulates, aerosols, 20 sprays or thermal fumigating mixtures in which the active • ingredient is associated with a solid pyrotechnic component -35 44373 41. Compositions as claimed in any of claims 29-40 in liquid form, in which the concentration of active ingredient is from 0.01 to 5 % by weight. 42. Compositions as claimed in claim 41 in which the 10 I as defined in claim 1 wherein and/or R 3 represents a chlorine or bromine atom. 32. Compositions as claimed in any of claims 29-31 which comprise as active ingredient a compound of formula I as defined in claim 1 wherein R 2 , R 3 and/or R^ represents a 15 methyl group. 33. Compositions as claimed in claim 30 which comprise as active ingredient a compound of formula I as defined in X 2 3 A 5 claim 1 wherein R , R ·, R , R* and R° all represent, hydrogen atoms. 20 34. Compositions as claimed In claim 30 which comprise as active ingredient a compound of formula I as defined in claim 1 wherein R represents a halogen atom and R , R , - 34 44373 10 steroid. 24. Compositions as claimed in claim 23 wherein the anti-inflammatory steroid is hydrocortisone. 25. Compositions as claimed in any of claims 2-24 which further contain an absorption promoting agent. 15 26. Compositions as claimed in claim 25 wherein the absorption promoting agent is dimethyl sulfoxide. 27. Pharmaceutical and veterinary compositions as claimed in claim 2 subsLactially as herein described. 28. Pharmaceutical and veterinary compositions 20 substantially as herein described in any one of Examples

10. Compositions as claimed in claim 3 which comprise N-prop-l-en-l-yl-3-hydroxy-pyrid-2-thione as active ingredient. 20 10 R , R and R each represent a hydrogen atom.

11. Compositions as claimed in claim 3 which comprise N-prop-2-en-2-yl-3-hydroxy-pyrid-2-thione as active ingredient . -31 44373 12. 5 with the proviso that R , R and R do not all represent hydrogen atoms when either one of R^ and R^ represents a hydrogen atom while the other represents a methyl group 3 4 or both R and R represent a hydrogen atom. 49. N-Vinyl-4-bromo-3-hydroxy-pyrid-2-thione. 50. N-Vinyl-4-chloro-3-hydroxy-pyrid-2-thione. 51. N-prop-2-en-2-yl-3-hydroxy-pyrid-2-thione, 52. N-Vinyl-6-chloro-3-hydroxy- pyrid-2-thione. 53. Trans-N-prop-l-on-l-y1-3-hydroxy-pyrid-2-thione substantially free from the cis -isomer thereof. 54. A process for the preparation of compounds of formula -37443^ 3 I as defined in claim 1 which comprises the reaction of a compound of the general formula:R 1

12. Compositions as claimed in claim 2 which comprise N-vinyl‘-6-chloro-3-hydroxy-pyrid-2-thione as active ingredient.

13. Compositions as claimed in any of claims 2-12 in a form suitable for topleal,nasal or aural administration.

14. Compositions as claimed in claim 13 in the form of creams, lotions, dusting powders, ear drops, nasal drops or in the form of spray compositions. 15. Compositions as claimed in claim 14 in the form of aerosol sprays, 16. Compositions as claimed in claim 14 in the form of creams, ointments and lotions which contain 0.2 to 5.0% by weight of the active ingredient of formula· I as defined in claim 1. 17. Compositions as claimed in claim 16 which contain from 0.5 to 2.0% by weight_of the said active Ingredient. 18. Compositions as claimed in claim 15 wherein the aerosol spray contains 0.02 to 1% by weight of the active ingredient of formula I as defined in claim 1. 19. Compositions as claimed in claim 18 which contain ‘ from 0.05 to 0.5% by weight of the said active ingredient. 20. Compositions as claimed in claim 14 in the form of dusting powders which contain 0.1 to 3.0% by weight of the active ingredient of formula I as defined in claim 1. 21. Compositions as claimed in claim 20 which contain 5 about 1% by weight of the said active ingredient. 22. Compositions as claimed in any of claims 2-12 in a form suitable for oral administration. 23. Compositions as claimed in any of claims 2-22 which further contain an other anti-microbial or anti-inflammatory

15. 70. Compounds of formula I as defined in claim 48 when prepared by a process as claimed in any of claims 65 to